1. Approach to Abnormal Liver Tests Anne Larson, MD Hepatology University of Washington

2. Anne Larson MD Case 1 – 65 y/o woman comes to you to establish care complaints fatigue pruritis dry eyes past history hysterectomy for fibroids 10 years ago no alcohol, tobacco or drug use

3. Anne Larson MD Case 1 – 65 y/o woman exam spider angiomata mild splenomegaly otherwise normal

4. Anne Larson MD Case 1 – 65 y/o woman screening labs reveal platelets 90,000-alk phos 4x uln bilirubin normal-albumin 3.3 (nl >3.5) AST/ALT normal-PT normal what do you want to do next? be thinking about this

5. Anne Larson MD Case 2 – 43 y/o female complaining of 4 days of prolonged, severe RUQ pain fever, severe nausea, some vomiting worse after eating Past History 20 yr ago began periodic attacks evening RUQ pain, fluctuating intensity, no fevers lasting 1-4 hours with residual RUQ tenderness

6. Anne Larson MD Case 2 – 43 y/o female Past History (cont) during last 8 years, continued episodes pain more intense and prolonged, accompanied by penetrating pain to back below scapula marked tenderness in RUQ persisting days told in the past she had gallstones

7. Anne Larson MD Case 3 Exam temp 38.5°C pulse 100 uncomfortable/sweating marked tenderness in RUQ with splinting (+) Murphy's sign icterus bilirubin 6 mg/dl-alk phos 3x nl (~400 U/L) ALT 100 mg/dl-normal albumin, PT WBC 28,000-GGT 150 U/L (nl <45) how would you proceed?

8. Anne Larson MD Approach to Abnormal Liver Tests If patient is asymptomatic The First Step: repeat the tests to confirm the results make sure to stop all alcohol use

9. Anne Larson MD The Diagnosis No single test is sufficient No single battery of tests is sufficient

10. Anne Larson MD The Diagnosis Most liver disease can be diagnosed by: taking a meticulous history recognizing the pattern of enzyme elevations rationally selecting a few “second-line” tests and imaging studies

11. Anne Larson MD Types of Liver Tests grouped by the liver function they assess measures of hepatobiliary cell injury measures of transport efficiency of organic compounds measures of hepatic synthetic function

12. Anne Larson MD Tests Reflecting Cell Injury Aminotransferases (ALT & AST) Alkaline Phosphatases Transpeptidases 5’-Nucleotidase

13. Anne Larson MD Tests Reflecting Cell Injury Aminotransferases Catalyze  -amino group transfers aspartate or alanine  ketoglutarate indicators of liver cell (hepatocyte) injury sensitive but not specific most useful marker of cell inflammation or necrosis represent a “leak” from damaged cells

14. Anne Larson MD Tests Reflecting Cell Injury Aminotransferases - cont aspartate aminotransferase (AST) in cytosol and mitochondria liver > heart > skeletal muscle > kidneys > brain > pancreas > lungs > WBCs > RBCs alanine aminotransferase (ALT) in cytosol predominantly liver more sensitive and specific than AST

15. Anne Larson MD Tests Reflecting Cell Injury Aminotransferases – cont. elevated in nearly all liver diseases (ALT > AST) marked  is usually hepatocellular disease levels may/may not reflect extent of damage do not correlate with eventual outcome usually <500 in obstructive jaundice usually parallel each other AST > ALT with EtOH, fulminant, and pregnancy

16. Anne Larson MD Tests Reflecting Cell Injury Alkaline Phosphatase catalyzes organic phosphate esters the enzyme is bound to hepatic canalicular membrane elevation may be due to induction of enzyme synthesis rather than inability of liver to secrete it into the bile increases seen with cell injury or obstruction slight to moderate (1-2x) – usually hepatocellular large increases (3-10x) – obstruction or cholestasis

17. Anne Larson MD Tests Reflecting Cell Injury Alkaline Phosphatase – cont. isolated elevations infiltrative disease – tumor, abscess, granuloma, amyloid Non-liver causes of elevations: bone disease»diabetes chronic renal failure»intestinal disease renal cancer»genetic (pseudoelevation) pregnancy»osteitis deformans sepsis (esp. GNRs)»multiple bone fractures Hodgkin's disease»intraabdominal infections hypothyroidism»pernicious anemia congenital hypophosphatasia »zinc deficiency

18. Anne Larson MD Tests Reflecting Cell Injury  -glutamyl transpeptidase (GGT) catalyzes transfer of  -glutamyl groups high concentrations in bile ductule epithelial cells useful to exclude “bone” source for Alk Phos correlates with alk phos levels in liver disease sensitive but not specific  in renal failure, MI, pancreatitis, diabetes

19. Anne Larson MD Tests Reflecting Cell Injury GGT – cont. Causes of elevations: liver disease»pancreatic disease alcohol»renal disease cardiac disease»obesity radiotherapy »diabetes drugs – GGT is “inducible” phenobarbital  anticoagulants dilantin  oral contraceptives acetaminophen  tricyclic antidepressants

20. Anne Larson MD Tests Reflecting Cell Injury 5’-Nucleotidase ( 5NT ) hydrolyzes 5’ phosphates from nucleotides associated with canalicular and sinusoidal membranes physiologic function unknown only hepatobiliary tissue can release 5’-NT specific for hepatic disease highest in cholestatic conditions

21. Anne Larson MD Tests Measuring Transport Efficiency Hepatic clearance reflects: 1.delivery to hepatocyte (blood flow) 2.uptake by hepatocyte

22. Anne Larson MD Tests Measuring Transport Efficiency Hemoglobin(1) Heme B-Alb (2) Other Tissue Cytochromes, etc. Alb

23. Anne Larson MD Tests Measuring Transport Efficiency Hepatic clearance reflects: 1.delivery to hepatocyte (blood flow) 2.uptake by hepatocyte 3.transport within hepatocyte 4.molecular alterations within hepatocyte

24. Anne Larson MD Tests Measuring Transport Efficiency Hemoglobin(1) Heme B (3)  Conjugated (4)  B-Alb (2) Other Tissue Cytochromes, etc. Alb

25. Anne Larson MD Tests Measuring Transport Efficiency Hepatic clearance reflects: 1.delivery to hepatocyte (blood flow) 2.uptake by hepatocyte 3.transport within hepatocyte 4.molecular alterations within hepatocyte 5.secretion by hepatocyte into bile 6.passage down bile ducts into duodenum

26. Anne Larson MD Tests Measuring Transport Efficiency Hemoglobin(1) Heme B (3)  Conjugated (4) Secreted(5) B-Alb (2) Other Tissue Cytochromes, etc. (6) Feces99% Urine1% Alb

27. Anne Larson MD Tests Measuring Transport Efficiency Hemoglobin(1) Heme B (3)  Conjugated (4) Secreted(5) B-Alb (2) Other Tissue Cytochromes, etc. (6) Feces99% Urine1% Alb

28. Anne Larson MD Tests Measuring Transport Efficiency Remember, hepatic clearance reflects: 1.delivery to hepatocyte  hemolysis 2.uptake by hepatocyte  shunts, drugs ( i.e., sulfa ) 3.transport within hepatocyte  drugs, genetics 4.molecular alterations within hepatocyte  genetics 5.secretion into bile  cell damage, genetics 6.passage down bile ducts  obstruction

29. Anne Larson MD Transport Efficiency Bilirubin derived mainly from hemoglobin ( 95% ) continuous production (300 mg daily) normal liver reserve can rev up 2-3 times normal values of “total” bilirubin = 0.1-1.0 mg/dL conjugated plus unconjugated direct plus indirect jaundice evident with levels >3.0 mg/dL

30. Anne Larson MD Tests Measuring Transport Efficiency Types of Bilirubin Direct BilirubinIndirect Bilirubin conjugatedunconjugated water solublelipid soluble polarnon-polar seen in urinenot in urine

31. Anne Larson MD Tests Measuring Synthetic Function Prothrombin Time (PT) Albumin Number Connection Tests / mental status The liver is the only source of albumin and the prothrombin group of clotting factors

32. Anne Larson MD Tests Measuring Synthetic Function Prothrombin Time (PT) sick liver can’t make clotting factors factors 2, 5, 7, 9, 10 (made only in the liver) prolonged PT reflects failure of liver synthesis Other causes of prolongation: congenital deficiencies consumptive coagulopathies (i.e., DIC) drugs (i.e., warfarin) vitamin K deficiency (i.e., dietary,  bile output)

33. Anne Larson MD Tests Measuring Synthetic Function Albumin most important plasma protein made by the liver accounts for 65% of protein in serum half-life ~17-21 days useful indicator of liver function Other causes of decrease : sepsis or multiple organ failure acute liver failure dietary

34. Anne Larson MD Tests Measuring Synthetic Function Number Connection Test liver is site of detoxification failure leads to toxins in blood toxins unknown encephalopathy is sign of liver synthetic failure

35. Anne Larson MD The Approach Important questions to address: acute vs. chronic (  6 months, ?cirrhosis) hepatocellular vs. cholestatic asymptomatic vs. symptomatic ?impaired function recent insults to the liver? EtOH, medications, pregnancy, hepatitis, herbs, gallstones, hypotension, toxins

36. Anne Larson MD The Approach Hepatocellular Injury mainly  AST & ALT +/-  AP, GGT, bilirubin  2 enzyme elevations  high likelihood of liver dz guides: Mild (<3 x normal) fatty liver, EtOH, chronic hepatitis Moderate (2-10 x normal) EtOH, chronic hepatitis, cirrhosis, neoplasm, gallstones Severe (>10x normal; usually >1,000) ischemic, viral, toxic (e.g., acetaminophen, herbs)

37. Anne Larson MD The Approach Cholestatic Liver Disease mainly alkaline phosphatase & GGT +/- bilirubin determine source of AP determine fraction of bilirubin elevated if all indirect, generally not liver ultrasound and/or CT scan to rule out obstructive disease, tumors, gallstones

38. Anne Larson MD The Approach Chronic Liver Disease  6 months of abnormal liver tests symptoms asymptomatic – majority of cases fatigue arthralgias pruritis jaundice

39. Anne Larson MD The Approach Chronic Liver Disease – cont. Common Causes – 95% of cases: Hepatitis C - (+) HCV-Ab and HCV-PCR Hepatitis B – (+) HBsAg and HBV-DNA Alcoholic liver disease Hemochromatosis – fasting Fe/TIBC >50%;  ferritin Autoimmune hepatitis – (+) ANA, (+) ASMA,  IgG

40. Anne Larson MD The Approach Chronic Liver Disease – cont. Less Common Causes Primary Biliary Cirrhosis (PBC) - (+) AMA;  IgM Primary Sclerosing Cholangitis (PSC) – abnormal ERCP Wilson’s Disease (  ceruloplasmin)  1 -Antitrypsin Deficiency (   1 AT level) Drugs (i.e., MTX, INH, amiodarone, methyldopa)

41. Anne Larson MD The Approach Chronic Liver Disease – cont. signs of cirrhosis spider angiomata gynecomastia portal hypertension (caput medusa) palmar erythema ( seen in 10-15% of normal population ) advanced end stage liver disease – refer pronto! ascites»  albumin varices»  prothrombin time encephalopathy

42. Anne Larson MD Case screening labs reveal platelets 90,000-alk phos 4x nl bilirubin normal-albumin 3.4 (nl >3.5) AST/ALT normal-PT normal what are the possible diagnoses? what do you want to do next?

43. Anne Larson MD Case 1 Further lab testing: HAV (-) HBV (-) HCV (-) ANA (-) ASMA (-) AMA (+) 1:1280 iron studies normal ultrasound – splenomegaly, small liver, no bil dil What Next?

44. Anne Larson MD Case Answer: primary biliary cirrhosis just beginning to decompensate  send for OLT

45. Anne Larson MD Summary No ideal study or battery to evaluate liver abnormal liver tests are often the first sign of liver disease normal or minimally elevated tests don’t exclude serious disease or cirrhosis liver biopsy remains the gold standard to detecting and determining cause of disease